Activin is a growth suppressive member of the TGFbeta super-family. It initiates its signaling via a specific receptor, activin receptor type 2 (ACVR2), that subsequently phosphorylates receptor type 1 to activate a signaling cascade via nuclear translocation of SMAD proteins. We show that mutation of ACVR2 occurs in 83% of primary colorectal cancers with high frequency microsatellite instability (MSI-H) leading to complete loss of protein expression due to a frameshift in an exon 10 polyadenine tract within ACVR2. Thus, the goal of this project is to understand the role of activin signaling in colon tumorigenesis. We hypothesize that defective ACVR2 causes abrogation of activin-induced growth suppression in colorectal cancer cells. We propose to study this hypothesis by utilizing a cell model where ACVR2-mutated colon cancer cells are complemented with a single copy of ACVR2. We will study the consequences of restored ACVR2 in colon cells through analysis of the activin signaling cascade, as well as transactivation and expression of downstream effectors; the effect of activin on cell growth and apoptosis, and modulation of the activin pathway by mitogenic signals that are simultaneously operative in colon cancer cells. We will also compare the relative contribution of loss of activin and TGFbeta signaling, since receptors for both pathways are often mutated in MSI-H colon cancers and both share SMAD cytoplasmic signaling proteins. Determining the role of activin signaling in colorectal cancers will further our insight into colorectal carcinogenesis and provide future targets to direct diagnosis and treatment. During the P.l.'s training , she was awarded a Fellow to Faculty Transition Award from the FDHN and has accepted a faculty position at UCSD effective 8/04. This proposal is designated to enhance the P.l.'s development as an independent physician-scientist by the end of the proposed funding period.